Relapse continues to plague public health efforts to reduce the prevalence of cigarette smoking. Recent evidence suggests that a large percentage of individuals attempting smoking cessation lapse to smoking within a matter of days, and few recover to achieve and maintain smoking abstinence. Results of studies relating severity of nicotine withdrawal symptoms to short-term smoking cessation outcomes have been equivocal. Instead of focusing on severity of withdrawal symptoms, we suggest that factors surrounding how one reacts to symptoms of nicotine withdrawal is more promising. In total, biological, physiological, emotional and behavioral responses to nicotine withdrawal constitute a type of biobehavioral reactivity that may convey vulnerability to early smoking lapse, and in a broader sense, may be an important component of dependence to nicotine. The overall aim of this study is to examine biobehavioral mechanisms related to early smoking lapse in a laboratory investigation of 84 cigarette smokers making an unaided smoking cessation attempt. The sample will be stratified by gender, level of nicotine dependence and history of major depression. Additionally, subjects will be followed for four weeks after attempting cessation, and based upon a median split of time to first smoking lapse, will be grouped as either early lapsers or sustainers. Prior to self-quitting, subjects will be exposed to three laboratory procedures to investigate biobehavioral reactivity to (a) a psychological stressor, (b) physical discomfort and (c) a neuroendocrine dexamethasone/corticotropin releasing hormone (DEX/CRH) challenge test. We expect that early lapsers will have higher levels of reactivity to these procedures on biological, physiological, affective and behavioral measures. Secondarily, we hypothesize that these biobehavioral measures of reactivity will be related to lifetime recurrent MDD, elevated measures of affective vulnerability, and elevated negative mood upon initial cessation. We expect that the results of this study will increase our basic knowledge about biobehavioral vulnerability factors in early smoking lapse and subsequent relapse in smokers quitting without professional assistance, a group that is understudied yet accounts for 90 percent of all cigarette smokers. Because early lapsers represent a recalcitrant group of smokers who are at-risk for continued nicotine dependence, these research findings should hold considerable clinical and public health significance and may result in the development of novel pharmacological and cognitive- behavioral treatments for nicotine dependence.